Women were not included in the study if they had comorbid
medical conditions or were taking medications that could affect bone,
declined study participation, or had underlying hip disease other than
osteoarthritis. Comorbid medical conditions included renal
insufficiency, creatinine level of 177 µmol/L (0.02 mg/dL) or more,
malabsorption, gastrectomy, active liver disease, acute myocardial
infarction, alcoholism, and anorexia nervosa.

Ray NF, Chan JK, Thamer M, Melton III LJ. Medical
expenditures for the treatment of osteoporotic fractures in the United
States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res.1997;12:24-35.

Webb A, Pillbeam C, Hanafin Not Available, Hollick M. An evaluation
of the relative contributions of exposure to sunlight and of diet to
the circulating concentrations of 25-hydroxyvitamin D in an elderly
nursing home population in Boston. Am J Clin Nutr.1990;51:1075-1081.

Design Comparative case series conducted between January 1995 and
June 1998.

Setting and Patients Ninety-eight postmenopausal
community-dwelling women with no secondary causes of bone loss admitted
for hip replacement, of whom 30 women had acute hip fractures and 68
women were admitted for elective joint replacement. Of the women
admitted for elective joint replacement, 17 had osteoporosis and 51 did
not. Women with comorbid conditions or who were taking medications that
affect bone density and turnover were excluded.

Main Outcome Measures Primary measures were levels of vitamin D
and parathyroid hormone; secondary measures were body composition and
markers of bone turnover.

Results Women with hip fractures had lower levels of
25-hydroxyvitamin D than women without osteoporosis admitted for
elective joint replacement (P=.02) and than
women with osteoporosis admitted for elective joint replacement
(P=.01) (medians, 32.4, 49.9, and 55.0 nmol/L,
respectively; comparisons adjusted for age and estrogen intake).
Parathyroid hormone levels were higher in women with fractures than
women in the nonosteoporotic control group (P<.001) or than
elective osteoporotic women (P=.001) (medians,
5.58, 3.26, and 3.79 pmol/L, respectively; comparisons adjusted for age
and estrogen intake). Fifteen patients (50.0%) with hip fractures had
deficient vitamin D levels (≤30.0 nmol/L) and 11 (36.7%) had a
parathyroid hormone level greater than 6.84 pmol/L. Levels of
N-telopeptide, a marker of bone resorption, were greater in
the women with hip fractures than in the elective nonosteoporotic
controls (P=.004).

Vitamin D is
required for efficient absorption of dietary calcium and for normal
mineralization of bone. Reduction in vitamin D levels is associated
with impaired calcium absorption and a compensatory increase in the
level of parathyroid hormone (PTH) which, in turn, stimulates bone
resorption and bone loss. According to the recent National Health and
Nutrition Examination Survey Study, an estimated 26 million to 38
million US adults have osteoporosis or are at risk for osteoporosis in
the hip.1 Risk of hip fractures increases exponentially
with age. Hip fractures are increasing worldwide, and are the most
devastating and costly of the osteoporotic fractures.2
Advancing age is associated with reductions in sun exposure, intake
and skin-activation of vitamin D, and in vitamin D absorption, all of
which may contribute to low vitamin D levels.3

It is striking that in recent studies from England, Scotland, and South
Africa, 13% to 33% of patients with hip fractures had histological
signs of osteomalacia that may have been caused by prolonged vitamin D
deficiency,4- 7 although not all European studies
concur.8 In the United States in 1978,
Sokoloff9 reported occult osteomalacia in 8 (25%) of 31
patients with hip fracture, and another study10 from an
elderly residential facility and hospital found 4 (12.9%) of 31
patients with osteomalacia at the time of hip fracture. Limited data
are available on vitamin D status in US patients admitted for acute
osteoporotic fractures. We compared such subjects with patients
scheduled for elective joint replacementsurgery to test the hypothesis
that patients with acute hip fractures have lower vitamin D levels and
higher PTH levels than do subjects without fracture with normal or even
low bone mineral density.

Methods

Patient Recruitment

A total of 805 postmenopausal women scheduled for joint replacement
were identified by daily monitoring of orthopedic admissions between
January 1995 and June 1998, including 262 women admitted to Brigham and
Women's Hospital with acute hip fracture and 543 women scheduled for
elective joint replacement either at the Brigham and Women's Hospital
or the New England Baptist Hospital in Boston, Mass. Postmenopausal
women who experienced either natural or surgical menopause with
amenorrhea for 12 months were recruited for this study. Women receiving
estrogen replacement therapy were included (46% of patients). Women
were excluded if they were taking any other medications or had any
disorders or abnormal admission test results that might affect bone, or
had any underlying hip disease other than osteoarthritis (Figure
1 and Table
1). Of the 68 women admitted for elective
joint replacement, 17 were determined to be osteoporotic (T score
<−2.5) according to the World Health Organization
bone density criteria11 and were analyzed separately
(elective osteoporotic group) from the 51 elective patients admitted
who were not osteoporotic (elective control group). There were 30
osteoporotic women with hip fractures (fracture group). Research
protocols were approved by the institutional review boards of the
Brigham and Women's Hospital and the New England Baptist Hospital.
All patients or, if necessary, a designated family member or guardian,
gave informed consent.

Bone mineral density of the spine (L1-L4), proximal femur, and total
body were measured with the dual x-ray absorptiometry technique
(QDR2000, Hologic Inc, Waltham, Mass). In vivo precisions (coefficient
of variation percentage) in postmenopausal women for the spine, femoral
neck, and trochanteric bone density measurements on different days were
1.21%, 1.74%, and 1.24%, respectively.14 Women with
vertebrae with moderately severe osteoarthritic changes, disk space
narrowing, or a fracture were excluded from the analyses as these
anatomic findings may elevate the spinal bone mineral density. Results
were expressed as SDs and compared with bone mineral density values for
age-matched healthy individuals (z score). Body composition
(lean and fat mass) was determined by dual x-ray absorptiometry
technique. The ratio of fat-to-lean tissue was calculated.
Reproducibility of mean (SEM) for fat and lean tissue determinations in
our laboratory were 1.09% (0.15%) and 0.89% (0.28%), respectively.

Blood Chemistries and Assays

Blood chemistries, complete blood cell counts, and tests for
urinary calcium levels were performed in hospital clinical
laboratories; all remaining tests were performed in the General
Clinical Research Center laboratory unless otherwise specified. Blood
samples were obtained preoperatively in 88% of the patients. In some
instances, elective or hip fracture patients were rushed to surgery and
informed consent and blood samples were obtained postoperatively. Serum
intact PTH levels were measured with the sensitive Allegro
immunoradiometric assay (Corning Nichols Institute, San Juan
Capistrano, Calif). Serum 25-hydroxyvitamin D levels were measured
using a radioimmunoassay (RIA) procedure (Incstar Corp, Stillwater,
Minn) approved by the Food and Drug Administration. Levels of
1,25-dihydroxyvitamin D were measured by RIA. Urinary
N-telopeptide levels, an index of bone resorption, were
determined in a 24-hour urine collection by an enzyme-linked
immunosorbent assay that measures cross-linked collagen peptides
(Osteomark Assay, Ostex International Inc, Seattle, Wash). Bone
formation markers including serum levels of osteocalcin by
RIA15 and bone-specific alkaline phosphatase (BSAP) were
measured by immunoradiometric assay (Tandem-R Ostase assay, provided
by Hybritech, San Diego, Calif) by Dr Gundberg of Yale University
School of Medicine, New Haven, Conn. The BSAP levels were measured by
immunoassay (Alphase B assay, provided, in part, by Metra Biosystems,
San Diego, Calif). The interassay and intra-assay coefficients of
variation for all the assays ranged from 2.3% to 12.1%.

Statistical Analyses

Patient characteristics and markers of bone turnover were
summarized as means and SDs. Analysis of variance was performed with
prespecified contrasts comparing the fracture group with each of the
elective groups, and having estrogen replacement therapy as a
covariate. Normality tests were rejected for several calciotropic
hormones, biochemical values, and baseline characteristics; therefore,
medians and 5th and 95th percentiles were presented. The natural log
transformed normalized intact PTH, 25-hydroxyvitamin D,
N-telopeptides, BSAP (Metra Biosystems), BSAP (Hybritech), and
creatinine. Analysis of variance was used for phosphate,
1,25-dihydroxyvitamin D, urinary calcium, transformed intact PTH,
25-hydroxyvitamin D, N-telopeptides, BSAP (Metra Biosystems),
BSAP (Hybritech), and creatinine, with age and estrogen replacement
therapy as covariates. Cochran Mantel-Haenszel tests were used for
albumin, total calcium, osteocalcin, total calcium intake, alcohol,
smoking, and physical activity with estrogen replacement therapy and
age above or below the median as stratification factors. Percentages
and χ2 tests were used to compare groups for dichotomized
calciotropic hormones. Ninety-one subjects had hip surgery and 7 had
knee surgery (6 from the elective control group, 1 from the elective
osteoporotic group). Results were nearly identical with and without
knee surgery subjects; combined results were presented. Analyses were
performed using SAS software (SAS Inc, Cary, NC).

Results

Patient Characteristics

Characteristics of 98 women who were enrolled in the study are
summarized in Table 2. The groups with osteoporosis (with fracture or
elective) did not differ in the years since menopause, and they had
comparable bone density levels (z scores) in the spine and
proximal femur sites, but they differed in total body bone density.
Body fat, percentage fat, and the fat-to-lean ratio showed monotonic
changes among the 3 groups. Compared with the elective control group,
the postmenopausal women admitted for hip fracture had reduced exercise
hours.

Circulating calcium levels were lower in the women with hip fractures
than in the elective control and osteoporotic groups (Table
3). Compared with the women in the control
group admitted for elective hip replacement, urinary
N-telopeptide levels were higher in the osteoporotic elective
and fracture groups (with similar z scores for the spine and
hip). Levels of N-telopeptide were not different between the
osteoporotic elective and fracture groups and were higher than the
elective control group. Osteocalcin, BSAP (Hybritech), and BSAP (Metra
Biosystems) were lower in women with fractures than in the elective
osteoporotic group. The correlation between the BSAP (Hybritech) and
the BSAP (Metra Biosystems) samples was 0.82 (Spearman rank
correlation, P<.001). Serum thyrotropin levels were
comparable among the 3 groups (data not shown). There were no
significant differences in calcium, albumin, phosphate, PTH,
25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, urinary calcium,
osteocalcin, creatinine, or N-telopeptide levels between
women whose serum sample was obtained preoperatively and the 12% of
women whose serum sample was obtained postoperatively.

Comment

This study shows low vitamin D and high PTH levels among elderly,
community-dwelling women in Boston admitted for acute hip fracture with
no secondary causes of bone loss. Half had vitamin D levels in the
deficient range (≤30 nmol/L) with high-range normal PTH levels or
secondary hyperparathyroidism. While there is increased awareness about
the importance of calcium nutrition for skeletal health, these data
suggest that deficient vitamin D levels should be of concern in women
admitted with hip fractures.

Circulating calcium and phosphate levels were lower in women with hip
fractures compared with those admitted for elective joint replacement,
consistent with vitamin D deficiency, impaired calcium and phosphate
absorption, and higher PTH levels. The higher PTH levels, in turn,
partially
raise circulating calcium to the lower limit of
the normal range and decrease the serum phosphate concentration. Low
albumin levels in women with hip fractures compared with the elective
groups may reflect nutritional status and are an independent predictor
of vitamin D deficiency in hospitalized subjects.16
Although we excluded patients from nursing homes and with comorbid
conditions affecting bone density, it is possible that the fracture
patients were more frail, had poorer nutritional status, and were
exposed to less sunlight than the control group.

Data were analyzed adjusting for estrogen replacement, as
indicated. Estrogen can affect bone and calciotropic hormones but
not 25-hydroxyvitamin D levels. Estrogen potentially can affect PTH
levels, but in women who were postmenopausal for less than 20 years (as
in the case, on average, for the elective subjects), PTH levels
increase with age. In women with more than 20 years since menopause,
similar to the women with hip fractures, estrogen may lower PTH levels.
Thus, estrogen use cannot account for higher PTH levels in women with
acute hip fracture compared with the elective groups. According to
Khosla et al,17 levels of vitamin D predict PTH levels
regardless of estrogen therapy or menopausal status. In our study, the
increase in PTH levels in postmenopausal women with hip fractures
cannot be explained by differences in creatinine level; the groups were
similar and no patient had a creatinine level above 159 µmol/L (1.8
mg/dL), a level at which intact PTH levels increase to more than 6.84
pmol/L.

Levels of 1,25-dihydroxyvitamin D did not differ between the
women with hip fractures and those admitted for elective joint
replacement. The conversion of 25-hydroxyvitamin D to
1,25-dihydroxyvitamin D in the kidney may be augmented in patients with
hip fractures by the stimulatory effects of higher PTH and lower
phosphate levels on renal 1-hydroxylation of vitamin D.18
Levels of vitamin D metabolites presented herein reflect the vitamin D
status at the time of hip fracture. One large study found low levels of
1,25-dihydroxyvitamin D but not 25-hydroxyvitamin D in women with hip
fractures, although the vitamin D metabolites were obtained
approximately 3.9 years before the fracture.19 Others did
not find low levels of 1,25-dihydroxyvitamin D in women with hip
fractures after correction for a decrease in vitamin D-binding
protein.

Osteoporosis results from an imbalance between bone resorption
and bone formation. The development of markers of bone turnover such as
the urinary N-telopeptide level, which is an index of bone
resorption, and serum osteocalcin and BSAP, which are bone formation
markers, make it possible to estimate bone remodeling noninvasively. In
our study, both the osteoporotic women admitted for elective orthopedic
surgery and those with hip fractures and comparable axial bone
density and years since menopause had higher
urinary N-telopeptide levels compared with the elective
women without osteoporosis. Levels of N-telopeptide,
osteocalcin, and BSAP increase with age and increased bone turnover is
a major determinant of osteoporosis in the elderly.20
Osteocalcin and BSAP levels were lower in the women with fractures than
women with osteoporosis in the elective group. This low osteocalcin
level in the women with hip fractures compared with the osteoporotic
elective group, in conjunction with higherN-telopeptide
levels, suggests an uncoupling of bone formation, with increased bone
resorption that may be a consequence of vitamin D deficiency. Another
study showed that urinary excretion of pyridinolines was higher in
elderly patients with vitamin D deficiency and elevated PTH levels than
in healthy young adults.21 Studies by Akesson et
al22 showed lower osteocalcin levels and higher urinary
pyridinoline levels in women with hip fractures than in age-matched
controls.

Several lines of evidence indicate that subclinical vitamin D
deficiency may contribute to increased fractures. First, there is
seasonal variation in vitamin D levels, with a decrease in winter and
spring that parallels the increased hip fracture rates during those
seasons.23 Second, the increase in PTH levels due to
vitamin D deficiency leads to PTH-mediated bone loss. Third, vitamin D
and calcium therapy reduce PTH and lead to a decrease in markers of
bone resorption, thereby reducing bone breakdown24,25 and
fractures.24,26

Low vitamin D levels and elevated PTH levels have been reported
in patients with hip fractures from Europe, Scandinavia, and
Australia.27- 29 However, in the United States, milk is
fortified with vitamin D so the intake of vitamin D is greater, and
vitamin D levels are higher than in Scandinavia and
Europe.30 Peacock et al31 determined that a
level of 25-hydroxyvitamin D of less than 9.98 nmol/L can cause
osteomalacia. Other studies show that a level of 25-hydroxyvitamin D
below 30.0 nmol/L is a threshold for decreased bone
density.32 Results may not be comparable, however, because
vitamin D assays used in earlier studies from Europe and Amsterdam had
lower values than the RIA assays now approved by the Food and Drug
Administration and often used in the United States.33,34
International standards for vitamin D assays and for normality are
needed for application to clinical care of patients with metabolic bone
disorders.

The decision to treat patients with low 25-hydroxyvitamin D
levels depends on the risk of a rise in PTH levels that may have
deleterious effects on the skeleton. For example, PTH levels increase
well before the 25-hydroxyvitamin D level decreases to 30.0 nmol/L (or
22.5 nmol/L, the lower limit of normal for some assays). A few
individuals were identified with 25-hydroxyvitamin D levels between
30.0 and 54.9 nmol/L and with elevated PTH levels. According to
different models, several 25-hydroxyvitamin D threshold levels for PTH
have been proposed. Ooms et al35 reported that
25-hydroxyvitamin D levels of 25.0 nmol/L are negatively related to PTH
and low bone density at a cutoff of 30 nmol/L. In elderly nursing home
patients including those in Boston, PTH levels were elevated with
25-hydroxyvitamin D concentrations less than 37.4 nmol/L, thus vitamin
D depletion was indicated by a 25-hydroxyvitamin D level below 37.4
nmol/L.3,36 Peacock et al31 defined vitamin D
deficiency as 25-hydroxyvitamin D levels between 9.98 and 49.9 nmol/L,
when there may be mild hyperparathyroidism and decreased bone
density.31 Chapuy et al37 studied 1569 French
subjects and found that PTH levels were s when the
25-hydroxyvitamin D level was higher than 77.4 nmol/L, using the same
RIA vitamin D assay used in our study. Haden et al38 also
showed that PTH levels start to increase at 25-hydroxyvitamin D levels
of less than 62.4 nmol/L. Thus, levels of 25-hydroxyvitamin D may need
to be higher than 49.9 to 73.4 nmol/L to protect against secondary
hyperparathyroidism.

Our study was not designed to assess seasonal changes and it did not
equally span all seasons in the study interval. The study may have
underestimated the frequency of low vitamin D levels in women with hip
fractures by excluding 190 subjects with comorbid conditions and
fractures who may have had reduced sun exposure and vitamin D intake (Table 1). A recent study showed that 57% of hospitalized patients had
low vitamin D levels.16

In conclusion, this study shows occult vitamin D deficiency
in postmenopausal women with hip fractures and no other secondary
causes of bone loss in the northeastern United States. Correction of
vitamin D deficiency or insufficiency with vitamin D supplementation or
sun exposure may lead to a reduction in the exponential rise of
fractures that occur with age. The new 1997 Dietary Reference Intake
guidelines from the National Institutes of Health recommend 400 IU of
vitamin D supplement daily for individuals from age 51 through 70 years
and 600 IU daily for those older than 70 years. Supplements of about
800 IU of vitamin D per day and calcium may be necessary to attenuate
bone loss in the winter and to reduce fractures.24,26 These
findings may play an important role in the orthopedic management of
acute fractures in postmenopausal women. In patients with hip
fractures, vitamin D repletion at the time of fracture and resultant
suppression of hyperparathyroidism may facilitate hip fracture repair,
implant incorporation, and reduction of future fracture risk.
Vitamin D deficiency is preventable and heightened awareness is
necessary to institute public health programs to ensure adequate
vitamin D nutrition in the elderly, particularly in northern
latitudes.

Ray NF, Chan JK, Thamer M, Melton III LJ. Medical
expenditures for the treatment of osteoporotic fractures in the United
States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res.1997;12:24-35.

Webb A, Pillbeam C, Hanafin Not Available, Hollick M. An evaluation
of the relative contributions of exposure to sunlight and of diet to
the circulating concentrations of 25-hydroxyvitamin D in an elderly
nursing home population in Boston. Am J Clin Nutr.1990;51:1075-1081.